Core Outcome Set development for LEPtospirosis trials (COS-LEP): a study protocol to develop a core outcome set for the evaluation of clinical therapeutic interventions for human Leptospirosis

Core Outcome Set development for LEPtospirosis trials (COS-LEP): a study protocol to develop a core outcome set for the evaluation of clinical therapeutic interventions for human Leptospirosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Core Outcome Set development for LEPtospirosis trials (COS-LEP): a study protocol to develop a core outcome set for the evaluation of clinical therapeutic interventions for human Leptospirosis Nathaniel Lee, Chris Smith, Robin Bailey, Koya Ariyoshi, Sarah Smith, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4900929/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Jan, 2025 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background Leptospirosis is a zoonotic bacterial infection occurring worldwide. It is of particular public health concern due to its global distribution, epidemic potential and high mortality without appropriate treatment. The method for the management of leptospirosis, particularly in severe disease, is clouded by methodological inconsistency and a lack of standardized outcome measures. The study this protocol details aims to develop a core outcome set (COS) for leptospirosis research. A COS is a set of outcomes with international consensus as a minimum for reporting in future studies focusing on leptospirosis. Establishing a COS will contribute to harmonizing Leptospirosis treatment research and will be instrumental in constructing a high-quality evidence base to feed into a planned future rigorous international clinical trial on leptospirosis. Methods The COS-LEP study will employ a COS development methodology standardized by the COMET initiative framework. This includes: 1) a systematic review of available quantitative and qualitative literature reporting therapeutic response and safety outcomes and measures; 2) focused interviews with healthcare professional and people treated for leptospirosis exploring outcomes of interests using qualitative methodology; 3) narrowing the choice of outcomes by international consensus using a Delphi survey process; and 4) undertaking a hybrid consensus meeting with key stakeholders to build the final COS. Discussion This protocol describes the method to develop the first core outcome set for use in human leptospirosis studies. This will not only be a key feature in the design of a future definitive randomised controlled trial, but also provide a structure for clinicians and researchers collecting treatment cohort data in the various settings where leptospirosis is a public health issue. Leptospirosis core outcome set clinical trial systematic review qualitative interview Delphi survey Figures Figure 1 Figure 2 Introduction Leptospirosis is a zoonotic bacterial infection occurring worldwide caused by Leptospira interrogans . Although sporadically reported in high income countries, low-and-middle income countries bear a high burden of cases – particularly in the South East Asian, Pacific, and Central and South American geographical areas.( 1 ) There are an estimated 1.03 million cases and 58,900 deaths due to Leptospirosis worldwide per year.( 2 ) More frequent climate catastrophes, poor infrastructure and social deprivation in these areas often precipitate outbreaks and epidemics.( 3 ) The diagnosis of leptospirosis is difficult. Clinical manifestations vary from mild to severe disease requiring hospitalization and organ-supported care. Early manifestations are of an acute febrile illness (mimicking the presentation of various systemic infections in the tropics) with 10% of infected patients developing severe disease, including manifestations of hepato-renal failure and pulmonary haemorrhage requiring intensive hospital care.( 4 ) The evidence for the management of leptospirosis particularly in severe disease, is limited by methodological inconsistency and a lack of established outcome measures to characterise disease and evaluate treatments. A 2012 Cochrane review of antimicrobial treatment included seven randomized trials spanning 1988–2007. The outcome measures used varied from mortality, length of hospital stay, urinary culture clearance, resolution of biochemical changes, and defervescence (i.e. resolution of fever). Despite four trials including individuals with severe disease, no definitions of severity were provided. Duration of symptoms varied at presentation in each study. The review concluded there was insufficient evidence to advocate for, or against, the use of antimicrobials due to poor methodological quality or underpowered studies.( 5 ) Similarly, when considering immunosuppressive therapies for severe leptospirosis disease, the last systematic review conducted in 2014 concluded there was insufficient data to establish efficacy.( 6 ) Outcomes measures varied for these studies and included death, duration of ventilation, and duration of bleeding. The establishment of core outcome sets (COS) to define outcome measures is increasingly important to improve relevance of clinical trials to health service users and policy makers.( 7 ) This is particularly vital for research activities involving neglected diseases, where robust methods must be established to ensure reliably comparable trial results in a consistent manner.( 8 ) To date there have been no COS established specifically for the clinical management of leptospirosis. Standardization of measures would add consistency and lead to harmonization of leptospirosis therapeutic trials, thereby reducing waste in production and reporting of research. Furthermore, there are currently no established primary efficacy or safety outcomes for a definitive clinical trial of leptospirosis treatments, a significant contributing factor to current inconclusive systematic reviews regarding treatment and which represents a neglected research area. The aim of this study protocol is to describe a study framework that will define the minimum agreed upon set of outcomes for any clinical therapeutic trial in human leptospirosis. Methods Scope To develop the COS-LEP protocol guidance set out by the Core Outcome Measures in Effectiveness Trials (COMET) initiative, and further specified by the Core Outcome Set-Standardised Protocol Items (COS-STAP) statement, were followed.( 1 , 9 , 10 ) These provide standardised frameworks for the development of a COS. The COMET database (available at https://www.comet-initiative.org/Studies ) was searched for any pre-existing COS protocols for leptospirosis. When it was confirmed that there were none, this protocol was then registered ( https://www.cometinitiative.org/Studies/Details/2536 ). The planned start date of the study is July 2024, and the end date is October 2025. Technical review has been provided as part of the London School of Hygiene and Tropical Medicine (LSHTM) formal institutional Qualifying Exam process for PhD programs. The population that will be targeted with this COS are any individuals working in healthcare who regularly look after patients diagnosed with leptospirosis disease, researchers and policymakers involved in leptospirosis research, and individuals or groups representing individuals who are at risk of or who have been diagnosed with leptospirosis disease. The project will be carried out in five distinct phases, summarized in Fig. 1 . The combined Phase 1 and 2 will consist of undertaking a systematic review of the literature for reported outcomes from quantitative and qualitative studies on the management of leptospirosis. In Phase 3, focused interviews to explore further outcomes of interest will be undertaken with healthcare providers and people at risk of leptospirosis infection. Phase 4 will consist of a multi-round Delphi survey process to begin constructing consensus around the outcome set. And Phase 5 will finalize the process with a consensus meeting. The schedule of enrolments and assessments is provided in Fig. 2 , as per Standard Protocol Items: Recommendations for Interventional Trials statement (SPIRIT).( 11 ) A SPIRIT checklist is provided as a supplementary document ( Supplementary 1 ). Figure 2 - SPIRIT figure detailing chronology of activities by study phase. Phase 1 and 2 Phase 1 and 2 will establish existing knowledge about outcomes and methodology used in previous quantitative and qualitative studies looking at the treatment of human leptospirosis. To explore outcomes, a systematic review of outcomes from previously published quantitative and qualitative studies will be undertaken. The protocol for this systematic review has already been registered with the PROSPERO system in detail (PROSPERO ID CRD42023397461). In addition, systematic Cochrane Library reviews will be completed exploring methodology of all known clinical trials for human leptospirosis treatment, and determine efficacy and safety outcomes reported to date for evaluations of therapeutic interventions.( 12 – 14 ) The output from all of these initiatives will provide the basis for options to put forward at later agreement stages. Study selection The following databases will be included in the search: the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, LILACS, Web of Science Core Collection, Clinicaltrials.gov, and OpenSIGLE. The latter will be particularly important for the identification of grey literature sources. In each identified study, forward and backward reference searching will be used to identify further relevant publications. Any study focusing on human leptospirosis will be included, across all age groups in a global distribution. Non peer-reviewed studies, most likely grey literature sources, may be considered. We will assess studies in batches chronologically by descending years in 5-year frames, until we achieve saturation in outcome types. Full manuscripts will be prioritised, but abstract-only publications may be considered particularly if the full publication is unable to be obtained from the publisher or manuscript author. The search will not be initially limited by language, but studies may be excluded depending on which languages reviewing authors are able to speak. Further requirements, as identified by the PRISMA-S checklist, will be applied.( 15 ) Data extraction Studies will be screened using the Covidence systematic review software ( https://www.covidence.org/ ). Title and abstract review, followed by full text review, will be performed by two reviewers. A third reviewer will be consulted if there is a disagreement between the first two reviewers that cannot be resolved through discussion. Data will be collected on the following; 1) Study design and sample size 2) Study population – demographics, location 3) Intervention 4) Outcomes 5) Outcome measurements instruments and/or definitions provided by the authors for each outcome 6) Study conclusions Quality Assessment The primary author will assess the quality of included studies in accordance to the QualSyst tool.( 16 ) Risk of bias in outcome reporting will be assessed according to the Outcome Reporting Bias in Trials (ORBIT) study classification system, and the ultimate goal will be to provide context to outcome measures rather than a basis for study exclusion.( 17 ) Data Analysis Data to be collected will be extracted verbatim. These will then be grouped based on terminology into group names, and then further grouped into domains.( 1 ) With respect to outcomes, as names and domains are dependent on the outcomes identified, these will not be defined a priori. A narrative synthesis of the included studies will be performed focused on the types of data collected defined above. The identified groupings will be mapped to the outcome framework proposed by the COMET group.( 1 ) Subgroup analysis will be considered if there are defined populations targeted by a particular outcome. Phase 2 specific considerations COMET handbook guidelines recommend the systematic review and identification of studies that specifically explore outcomes important to health service users.( 1 ) These may either be in the form of previously published Patient Reported Outcome Measures (PROMs) or studies employing qualitative methodology. It is not expected that a significant number of qualitative studies exploring treatment outcomes or studies establishing PROMs for leptospirosis have been previously published. If identified, a similar study selection and appraisal process as described in Phase 1 will be employed, focused on studies with a qualitative or mixed-methods design (where qualitative data collection and analysis methods were employed). With regards to data extraction, previously published methodology for extracting and analysing outcomes from studies reporting PROMs ( 18 ) and qualitative literature ( 19 – 22 ) will be used. Concepts and themes from excerpts will be categorized and tabulated to obtain frequency information. Categories will be mapped against the proposed COMET taxonomy, and if multiple domains are appropriate then two domains will be chosen as per guidance and precedence.( 1 , 20 ) Phase 3 Central to the COS-STAP statement is the definition of stakeholder groups who will be involved in the COS development process including how individuals will be identified, and the nature of their involvement.( 9 ) This is particularly important as it is expected that identification of PROMs through the systematic review of qualitative literature may not yield many results. Therefore Phase 3 will involve exploring outcomes of interest with healthcare providers and end-users directly affected by leptospirosis, to identify outcomes important to these groups, through the use of qualitative methods. This will, in addition, identify target population groups, explore acceptability of therapeutic interventions, and assess feasibility of conducting trial activities. Participants Recruitment and Sample Size Participant identification and recruitment will be done from collaborative institutional sites in the COS-LEP network. The institutions in the network are secondary/tertiary hospitals primarily found in areas endemic for leptospirosis – the Philippines, Malaysia, Vietnam, New Caledonia, and Brazil. This may extend to other institutional sites in the same or different countries during the COS study (with appropriate local ethics agreements obtained prior to any enrolment activities). Participants who are healthcare providers that manage patients with leptospirosis will be identified and approached for recruitment. Additionally those at risk of leptospirosis, or who have made contact with healthcare services and for whom leptospirosis is included in the differential diagnosis, will also be identified and approached for recruitment. They will be provided with a patient information leaflet, as well as a verbal description of the study and its intention. After a 24 hour consideration period, they will be approached again and consented for enrolment. Purposive sampling will be employed. Sample size calculations is a point of contention in qualitative studies, but methodological literature recommends that the reasoning behind any calculation be made transparent.( 23 ) Recent qualitative studies exploring individual perspectives of participant’s experience with leptospirosis disease have contained < 10 participants( 24 , 25 ). Since focused interviews and thematic analysis will be used, and we will aim to recruit from international sites where collaborative institutional research is currently ongoing, we will aim to recruit at least 6 participants from each site. This may be revised should further sites be identified. The overall aim will be to achieve theoretical sufficiency, as defined as a point when a researcher has achieved sufficient or adequate depth of understanding to build a theory.( 23 , 26 ) In addition, the total predicted sample size would approximate or supersede that of other COS-related published research using focused interviews.( 24 , 27 ) Data Collection Focused interviews will be conducted, aided by a general topic guide. These will either be in person or remote/via teleconferencing means, the latter which now has a growing body of evidence supporting its use in qualitative methodology.( 28 ) For those wishing to participate, but have limited fluency in English, attempts will be made to provide an interpreter subject to availability of personnel and/or funding. A very broad topic guide will be used, but the interview will be guided primarily by participants. Interviews will be audio recorded, and then anonymized and transcribed using the NVivo software (QRS International). Once all transcriptions are complete, interview recordings will be securely destroyed. Data Analysis Thematic analysis will be employed to summarize transcripts.( 29 ) Features in the transcripts involving outcomes will be coded, subsequent codes collated into potential themes, themes revised and then defined. The generated themes will then be mapped to against the proposed taxonomy as stated in the COMET handbook, although consideration will be made to include if there is no adequate classification. Common themes in the classifications will be identified and outcome definitions that closely approximate each other will be removed. Phase 4 The next stage of the COS development process will obtain a broad consensus on the proposed set of core outcomes identified in Phase 1–3. The recommended methodology to accomplish this is the Delphi technique targeted at experts and other stakeholders through the use an evolving questionnaire and multiple rounds of consensus surveys.( 1 ) Participant Recruitment and Sample Size The stakeholders of interest for participation in surveys are patients (those who experienced leptospirosis disease), infectious diseases healthcare professionals (including medical microbiologist), non-infectious diseases healthcare professionals (including nephrology, pulmonology, intensive care, family medicine or other specialties), allied global health researchers (including epidemiologists, trialists, statisticians, and one health), and policymakers (both governmental and non-governmental). As many stakeholders as possible in a worldwide geographic spread will be included. Guidance on total number of stakeholders to be included is not based on statistical power but a pragmatic choice.( 1 ) We will seek to include sufficient participants per group to achieve good representation, but which will still allow for a consensus within group to be achieved. Stakeholders will be approached for recruitment using several communication avenues both in-person and virtual. Participation in surveys will be advertised to patients by direct means (at collaborative sites and those identified during Phase 3), dissemination through hospital communications at collaborative sites, through a project-specific website, and through social media. Researchers active in human leptospirosis will be identified from studies collated in Phase 1–2 of the COS process. Healthcare professionals of any specialities will be identified by direct means at collaborative sites and through various professional networks of research teams. Policymakers will be identified through recommendation, existing national/international leptospirosis guidance, and from committee membership or involvement on various international leptospirosis societies. All participants will be requested to disseminate information through their various networks in order to increase uptake. Potential participants expressing interesting in taking part in the survey will be directed to a study page provided by the Qualtrics platform that will provide study information in lay terms with full definition of medical terminology if used. Basic information such as demographics and suitability to participate will be assessed if potential participants wish to proceed. If these are met, then they will be able to proceed to the Delphi survey, with consent being gained electronically before undertaking the questionnaire. Data Collection The COMET Initiative has offered guidance that at least two survey rounds take place in order to incorporate feedback.( 1 ) The minimum number of rounds for this study will be two but will be extended if further consensus is required. The survey will be built using the Qualtrics survey software ( https://www.qualtrics.com ) with a focus on lay language minimizing medical jargon (or with definitions included). We will attempt to engage with patients/members of the public identified from previous Phases of the COS-LEP study to develop and trial this lay terminology. Translations into other languages for particular groups will be explored depending on the participant groups included. Trials of the survey will be run amongst the study group and colleagues, and feedback incorporated back into the survey design. The COMET initiative suggests the use of the 9-point Likert scale where outcomes are graded in accordance to their level of importance, which is also the recommended framework by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group.( 1 , 30 ) This uses a scale between 1 and 9, with number 1–3 defined as outcome of limited importance, 4–6 outcome of importance but not critical, and 7–9 meaning critical outcome. There will be an additional grade of “Unable to score” should participants feel they do not have the level of expertise to score a certain outcome.( 1 ) The order of outcomes to be scored might introduce a bias, and so outcomes order will be randomized as used in other COS studies.( 20 ) Space will be provided at the point of rating each outcome and at the end of the questionnaire for participants to list additional outcomes not considered or to provide feedback on the list of outcomes. These will be reviewed between rounds by the study group and select patient representatives to determine classification within COMET taxonomy, how different the proposed outcome is from the existing listed outcome, and ultimately whether appropriate for inclusion in next round. There is wide variability in definition of whether individual outcomes meet a consensus for inclusion or exclusion of subsequent surveys, or at the end of the study. The COMET handbook does not provide a clear framework, but suggests more inclusive criteria be used in subsequent survey rounds should items be excluded in the intervening period.( 1 ) Relevant results from the first survey round will be presented to participants in the second round, presented graphically and by stakeholder group. This will enable participants to compare their prior scores within their stakeholder group and with other groups in the survey process. This study will adopt criteria used in previous COS studies, with less stringent criteria in earlier rounds.( 20 , 31 – 33 ). Common in all rounds will be 1) the definition of consensus out from next round, which is any outcome with ≥70% of all participants rated 1–3 (not important) for an outcome in any round; 2) any score not meeting inclusion or exclusion criteria will defined as no consensus; and 3) A participant’s score will be included for analysis if they complete 70% or more of outcomes. • Round 1. Inclusion in next round – any outcome rated 7–9 (critical outcome) by > 50% of any participant and 1–3 (limited importance) by no more than 15% of any single stakeholder group. • Round 2. Inclusion - any outcome rated 7–9 (critical outcome) by > 70% of any participant, and 1–3 (limited importance) by no more than 15% of any single stakeholder group. Should there remain a large number of outcomes following two rounds as decided by the study group a further third survey round may be conducted, with the outcome inclusion criteria to take forward to a consensus meeting being as for Round 2. Addressing Attrition There is a risk of non-response by participants at all stages of the Delphi process, likely made greater by the international scope of the study. In order to decrease rate of non-responses, surveys will be kept open for four weeks and up to three reminder e-mails per round will be sent to participants with incomplete surveys. Details of current response rate and reminders of survey closing dates will be included in each message. If response rates remain low, consideration will be made for additional measures to increase this with consideration to time and funding. We will aim for 80% response per stakeholder group. Data Analysis The distribution of outcomes for inclusion moving forward and degree of consensus will be summarized at the end of each round.( 1 ) Means and medians for each outcome will be calculated. The change of scores between rounds will be assessed by change in percentage, reduction in spread of scores by comparing standard deviations, and reductions in interquartile range.( 1 ) Metric will be reported for all participants, and inter-group between stakeholders. Phase 5 The final phase of the COS development process will involve a consensus meeting where representatives of the various stakeholder groups can convene to discuss the results of the survey and decide on a final core set. Although we will aim for an in-person meeting, given the international scope of this study and the distribution of the stakeholder group, we may explore the possibility of conducting a hybrid approach of virtual and in-person meeting. If using a hybrid meeting approach, we will use guidance published by the COMET Initiative.( 34 ) Participant Recruitment and Sample Size Building on standard proposed by the CODECS study, we will aim for 20 participants (4 from each stakeholder group to allow consensus to be achieved based on our revised consensus criteria) will be purposively selected for inclusion in a minimum of one consensus meeting.( 20 ) We will adjust this number depending on interest and the practicalities/logistics of attending an in-person meeting. Although any participant may be included, to provide transparency in selection the final Delphi survey round will include a query of whether a participant is able to attend the consensus meeting. Consideration will also be made to include participants who did not respond or dropped out during the Delphi survey. We will explore the possibility of using break-out groups depending on total group size and availability of facilitators who can be trained to moderate as used in other COS development studies.( 35 ) The final number of participants and number of meetings will be a pragmatic decision based on expressed interest in participation, feasibility of joining a meeting, and ensuring representative input from all participants. Data collection The consensus meeting will consist of an introduction of the aims of the COS-LEP study, a summary of Phase 1–4 activities and results, the discussions of the final set of outcomes, and a final vote on outcomes. The meeting will be recorded and take place over 2–3 hours, but may be longer or divided into sessions depending on the number of participants, availability, and number of outcomes. Outcomes to be discussed will primarily be those that were selected in the Phase 4 Delphi survey, but outcomes which were excluded may be re-introduced and discussed again depending on participant interest. Within each stakeholder group > 70% votes for either direct inclusion or exclusion of outcomes will be considered consensus. If there are issues with total number of participants or a limited number of stakeholder groups attending, we may consider using a threshold of > 70% across the entire group. These criteria have been proposed by the COMET Initiative as well as other COS developers such as the Outcome Measures in Rheumatology (OMERACT) group.( 10 , 36 , 37 ) Results will be presented after voting, and reported by stakeholder group as well as across the entire group. Outcomes which are excluded or which do not meet the criteria of consensus can be reviewed by participants where there is opportunity to discuss any reason to disagree with these results. Should the number of included outcomes be large, a method to classify these following previous examples such as composite or tiered outcomes will be discussed in group.( 37 , 38 ) Time permitting, the meeting may also be used to agree outcome definitions and define outcome measures.( 1 ) The meeting will be transcribed and analysed using thematic analysis to explore participant’s perspectives on the agreed core outcomes, barriers to implementing, and any recommendation or suggestions for proceeding.( 39 ) The outcome of Phase 5 will be the final core outcome set. Dissemination of Results The complete results of the COS study will be reported in international peer-reviewed open-access journals, international and national scientific and policymaking meetings, shared to clinical trial registries, and directly through all study group and participant networks. All study reports will follow reporting standards defined in the COS-STAR statement.( 7 ) Discussion The COS-LEP study protocol describes the establishment of a COS for human interventional trials in leptospirosis disease. As highlighted earlier, the clinical management of leptospirosis is complicated by inconsistent trial methodology in published studies to date. To the authors’ knowledge, this is the first COS developed for leptospirosis trials, and can serve as a template should such standards be required in the field of animal health. This COS will ensure that a minimum set of outcomes are included in any human leptospirosis trial. The use of these outcomes will have been agreed upon by healthcare professionals, policymakers, and patients. In this manner, the methodology of future trials can be harmonized and allow for easier and more meaningful comparison of results, particularly if undertaking meta-analysis. It will also be of benefit to the international treatment centres that manage leptospirosis cases and wish to record harmonised patient data. Trial Status This protocol version number is v11.0 (dated 9/8/2024). Systematic reviews quantitative and qualitative literature are in progress. Development of core outcome set is ongoing. Abbreviations COS; Core Outcome Set COMET; Core Outcome Measures in Effectiveness Trials COS-STAP; Core Outcome Set-Standardised Protocol Items PROMs; Patient Reported Outcome Measures COS-STAR; Core Outcome Set–STAndards for Reporting Declarations Ethics approval, confidentiality, and consent to participate Ethical approval has been received by the LSHTM Observational Research Ethics Committee (LSHTM Ethics Ref 29935). Approval for Phase 3 qualitative studies will be sought from relevant institutional review boards (IRB) prior to initiating study activities. Any planned protocol amendments will be communicated directly to the LSHTM Observational Research Ethics Committee and relevant local IRBs, with approval for amendments completed prior to any changes being instituted. Consent to participate in interviews, Delphi surveys, and consensus meeting will be requested by the primary investigator when enrolling participants for this process. For study phases where participants will be enrolled (Phase 3 and 4), participants data will be anonymized through assigning a participant number as soon as enrolled on the study. A master spreadsheet will be kept during the study linking the participant to the study number, this will be kept password-protected with limitation to which research personnel can access. After a maximum of 12 months from the end of data collection activities the master spreadsheet linking participants to study numbers will be destroyed (i.e. datasets with participant-identifying information will be destroyed). Anonymised datasets (e.g. anonymised transcripts) will be retained until the point where they are deposited in a data repository. Consent for publication Not applicable Availability of data and materials All authors will have equal access to data collected, and data will be deposited is a suitable repository at the end of the process. The protocol and individual studies will be made open-access. Competing interests The authors declare that they have no competing interests Funding This research was partially funded by the Nagasaki University WISE Programme in pursuit of a PhD qualification. The funding body did not contribute to the study. Authors’ contributions NL is the lead author and principal investigator, conceived of the study, wrote the primary and subsequent drafts of the protocol, and approved the final draft. TE contributed to the conception of the study and contributed to drafts of the protocol. CS contributed to the conception of the study and contributed to drafts of the protocol. RB contributed to the conception of the study and contributed to drafts of the protocol. KA contributed to the conception of the study and contributed to drafts of the protocol. SS contributed to the methodology of Phase 2 and 3, and reviewed the final protocol draft. NB contributed to the Phase 4 and 5 methodology, and reviewed the final protocol draft. Acknowledgements The authors would like to acknowledge the establishment of the COS-LEP study group in this protocol. Subsequent published results of COS-LEP phases will be attributed to the COS-LEP study group. The authors would like to acknowledge Dr Sarah Gorst (COMET Initiative, Institute of Population Health, University of Liverpool) for their technical review and advice on overall protocol. Author’s information NL is completing this project in pursuit of a PhD qualification on the Nagasaki University – London School of Hygiene and Tropical Medicine Joint PhD Programme for Global Health. The COS-LEP project has undergone technical review by an LSHTM MPhil/PhD Upgrading Committee on 19/12/2023. TE, CS, RB, and KA are PhD supervisors for the project. SS and NB form part of the PhD advisory committee. References Williamson PR, Altman DG, Bagley H, Barnes KL, Blazeby JM, Brookes ST, et al. COMET Handbook: Version 1 0 Trials. 2017;18(Suppl 3):1–50. Costa F, Hagan JE, Calcagno J, Kane M, Torgerson P, Martinez-Silveira MS, et al. Global Morbidity and Mortality of Leptospirosis: A Systematic Review. PLoS Negl Trop Dis. 2015;9(9):0–1. Costa F, Hagan JE, Calcagno J, Kane M, Torgerson P, Martinez-Silveira MS, et al. Global Morbidity and Mortality of Leptospirosis: A Systematic Review. PLoS Negl Trop Dis. 2015;9(9):0–1. Levett PN, Leptospirosis. Clin Microbiol Rev. 2001;14(2):296–326. Brett-Major DM, Coldren R. Antibiotics for leptospirosis. Cochrane Database Syst Rev. 2012;2(2):CD008264. Rodrigo C, Lakshitha de Silva N, Goonaratne R, Samarasekara K, Wijesinghe I, Parththipan B, et al. High dose corticosteroids in severe leptospirosis: a systematic review. Trans R Soc Trop Med Hyg. 2014;108(12):743–50. Kirkham JJ, Gorst S, Altman DG, Blazeby JM, Clarke M, Devane D, et al. Core Outcome Set–STAndards for Reporting: The COS-STAR Statement. PLoS Med. 2016;13(10):1–11. Olayinka AT, Bourner J, Akpede GO, Okoeguale J, Abejegah C, Ajayi NA, et al. A standardised Phase III clinical trial framework to assess therapeutic interventions for Lassa fever. PLoS Negl Trop Dis. 2022;16(1):1–14. Kirkham JJ, Gorst S, Altman DG, Blazeby JM, Clarke M, Tunis S, et al. Core Outcome Set-STAndardised Protocol Items: The COS-STAP Statement. Trials. 2019;20(1):1–7. Williamson PR, Altman DG, Bagley H, Barnes KL, Blazeby JM, Brookes ST, et al. COMET Handbook: Version 1 0 Trials. 2017;18(Suppl 3):1–50. Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346. Tabei K, Win TZ, Kitashoji E, Brett-Major DM, Edwards T, Smith C, et al. Antibiotic prophylaxis for leptospirosis. Cochrane Database Syst Reviews. 2022;2022:2. Mukadi P, Tabei K, Edwards T, Brett-Major DM, Smith C, Kitashoji E, et al. Antibiotics for treatment of leptospirosis. Cochrane Database Syst Reviews. 2022;2022:5. Win TZ, Tabei K, Mukadi P, Edwards T, Smith C, Lee N. Corticosteroids for treatment of leptospirosis. Cochrane Database Syst Reviews. 2022;2022(7). Rethlefsen ML, Kirtley S, Waffenschmidt S, Ayala AP, Moher D, Page MJ, et al. PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews. Syst Rev. 2021;10(1):39. Graham JW, Cumsille PE, Elek-Fisk E. Methods for Handling Missing Data. Res Methods Psychol. 2003;87–114. Kirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, Smyth R, et al. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews. BMJ (Online). 2010;340(7747):637–40. Macefield RC, Jacobs M, Korfage IJ, Nicklin J, Whistance RN, Brookes ST et al. Developing core outcomes sets: Methods for identifying and including patient-reported outcomes (PROs). Trials. 2014;15(1). Gorst SL, Young B, Williamson PR, Wilding JPH, Harman NL. Incorporating patients’ perspectives into the initial stages of core outcome set development: A rapid review of qualitative studies of type 2 diabetes. BMJ Open Diabetes Res Care. 2019;7(1). Richardson E, McEwen A, Newton-John T, Manera K, Jacobs C. The Core Outcome DEvelopment for Carrier Screening (CODECS) study: protocol for development of a core outcome set. Trials. 2021;22(1):1–11. Hoppe LE. Qualitative systematic reviews to increase the volume and diversity of patient perspectives included in the development of core outcome sets. Tuberculosis: a pilot study. Trials. 2015;16(S1). Froud R, Patterson S, Eldridge S, Seale C, Pincus T, Rajendran D et al. A systematic review and meta-synthesis of the impact of low back pain on people’s lives. 15, BMC Musculoskelet Disord. 2014. Konstantina Vasileiou J, Barnett S, Thorpe T, Young. Characterising and justifying sample size sufficiency in interview-based studies: systematic analysis of qualitative health research over a 15-year period. BMC Med Res Methodol. 2018;18(1):1–18. Martins MHdaM, Spink MJP. Discourse Analysis of the Attributions of Causality and Responsibility for the Occurrence of Leptospirosis TT - Análise Discursiva das Atribuições de Causalidade e Responsabilidade pela Ocorrência da Leptospirose TT - Análisis Discursivo de Asignaciones. Paidéia (Ribeirão Preto, Online). 2020;30:e3027–3027. Benschop J, Mocke S, Collins-Emerson JM, Lennan J, Weston JF. An exploratory qualitative enquiry into workers’ experiences of leptospirosis and post-leptospirosis in Aotearoa New Zealand. N Z Med J. 2023;136(1570):30–41. Braun V, Clarke V. Conceptual and Design Thinking for Thematic Analysis. Qualitative Psychol. 2021;9(1):3–26. Richardson E, McEwen A, Newton-John T, Crook A, Jacobs C. Outcomes of Importance to Patients in Reproductive Genetic Carrier Screening: A Qualitative Study to Inform a Core Outcome Set. J Pers Med. 2022;12(8). Archibald MM, Ambagtsheer RC, Casey MG, Lawless M. Using Zoom Videoconferencing for Qualitative Data Collection: Perceptions and Experiences of Researchers and Participants. Int J Qual Methods. 2019;18:1–8. Braun V, Clarke V. Usin thematic analysis in psychology. Qual Res Psychol. 2006;3(2):77–101. Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol. 2011;64(4):395–400. Lee SI, Eastwood KA, Moss N, Azcoaga-Lorenzo A, Subramanian A, Anand A, et al. Protocol for the development of a core outcome set for studies of pregnant women with pre-existing multimorbidity. BMJ Open. 2021;11(10):1–8. Brown V, Moodie M, Tran HNQ, Sultana M, Hunter KE, Byrne R, et al. Protocol for the development of Core Outcome Sets for Early intervention trials to Prevent Obesity in CHildren (COS-EPOCH). BMJ Open. 2021;11(7):1–8. Mitchell JW, Noble A, Baker G, Batchelor R, Brigo F, Christensen J, et al. Protocol for the development of an international Core Outcome Set for treatment trials in adults with epilepsy: the EPilepsy outcome Set for Effectiveness Trials Project (EPSET). Trials. 2022;23(1):1–8. Gorst S, Barrington H, Brookes S, Chalmers J, Devane D, Fledderus A et al. Online consensus meetings for COS development: issues to consider [Internet]. [cited 2024 Mar 9]. https://www.comet-initiative.org/Downloads/Issues%20to%20consider%20for%20online%20consensus%20meetings.pdf Manera KE, Tong A, Craig JC, Brown EA, Brunier G, Dong J, et al. Standardized outcomes in nephrology—peritoneal dialysis (SONG-PD): Study protocol for establishing a core outcome set in PD. Perit Dial Int. 2017;37(6):639–47. Boers M, Kirwan JR, Wells G, Beaton D, Gossec L, D’Agostino MA, et al. Developing core outcome measurement sets for clinical trials: OMERACT filter 2.0. J Clin Epidemiol. 2014;67(7):745–53. Beaton D, Maxwell L, Grosskleg S, Shea B, Tugwell P, Bingham CO III et al. The OMERACT Handbook Version 2.1 [Internet]. 2.1. Beaton D, Maxwell L, Grosskleg S, Shea B, Tugwell P, editors. OMERACT; 2021 [cited 2024 Mar 8]. https://omeract.org/handbook/ Bourner J, Salam AP, Jaspard M, Olayinka A, Fritzell C, Goncalves B et al. The West Africa Lassa fever Consortium pre-positioned protocol for a Phase II/III adaptive, randomised, controlled, platform trial to evaluate multiple Lassa fever therapeutics. Wellcome Open Res [Internet]. 2023;8:122. https://wellcomeopenresearch.org/articles/8-122/v1 Manera KE, Tong A, Craig JC, Brown EA, Brunier G, Dong J, et al. Standardized outcomes in nephrology—peritoneal dialysis (SONG-PD): Study protocol for establishing a core outcome set in PD. Perit Dial Int. 2017;37(6):639–47. Supplementary Files LeeCOSLEPSPIRTIchecklist.docx Cite Share Download PDF Status: Published Journal Publication published 06 Jan, 2025 Read the published version in Trials → Version 1 posted Editorial decision: Minor revision 11 Nov, 2024 Reviewers agreed at journal 23 Aug, 2024 Reviewers invited by journal 20 Aug, 2024 Editor assigned by journal 20 Aug, 2024 First submitted to journal 12 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4900929","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":342738972,"identity":"7900e54d-6885-4761-b345-12746bd468e1","order_by":0,"name":"Nathaniel Lee","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-4393-6891","institution":"London School of Hygiene \u0026 Tropical Medicine","correspondingAuthor":true,"prefix":"","firstName":"Nathaniel","middleName":"","lastName":"Lee","suffix":""},{"id":342738973,"identity":"4f7c75e0-c7b1-4790-8b4d-39ddc29c6b9d","order_by":1,"name":"Chris Smith","email":"","orcid":"","institution":"London School of Hygiene \u0026 Tropical Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chris","middleName":"","lastName":"Smith","suffix":""},{"id":342738974,"identity":"95952f1b-4119-4c7b-8f0f-4ef9d827da96","order_by":2,"name":"Robin Bailey","email":"","orcid":"","institution":"London School of Hygiene \u0026 Tropical Medicine","correspondingAuthor":false,"prefix":"","firstName":"Robin","middleName":"","lastName":"Bailey","suffix":""},{"id":342738975,"identity":"13acecb3-1119-4f32-87e2-ecb86c4b7ab8","order_by":3,"name":"Koya Ariyoshi","email":"","orcid":"","institution":"Nagasaki University School of Tropical Medicine and Global Health: Nagasaki Daigakuin Nettai Igaku Global Health Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Koya","middleName":"","lastName":"Ariyoshi","suffix":""},{"id":342738976,"identity":"2150a4d2-1004-4fe6-a291-90dbce591cc5","order_by":4,"name":"Sarah Smith","email":"","orcid":"","institution":"London School of Hygiene \u0026 Tropical Medicine","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Smith","suffix":""},{"id":342738977,"identity":"802b0da8-7900-446c-8321-d4ef773480b5","order_by":5,"name":"Nick Black","email":"","orcid":"","institution":"London School of Hygiene \u0026 Tropical Medicine","correspondingAuthor":false,"prefix":"","firstName":"Nick","middleName":"","lastName":"Black","suffix":""},{"id":342738978,"identity":"2093d7b7-9a17-44f1-828d-9a7c38f4bc59","order_by":6,"name":"Tansy Edwards","email":"","orcid":"","institution":"London School of Hygiene \u0026 Tropical Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tansy","middleName":"","lastName":"Edwards","suffix":""}],"badges":[],"createdAt":"2024-08-12 13:36:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4900929/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4900929/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-024-08713-6","type":"published","date":"2025-01-06T15:57:08+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":64783749,"identity":"e4ccb02a-9b94-46e4-92ae-10ccc3f5280a","added_by":"auto","created_at":"2024-09-18 18:59:14","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":89590,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of COS-LEP study\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4900929/v1/4a8af9e426ae6d95f124f130.jpg"},{"id":64783806,"identity":"f63637b4-14ed-4870-a495-bc5458a8761a","added_by":"auto","created_at":"2024-09-18 18:59:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":64514,"visible":true,"origin":"","legend":"\u003cp\u003eSPIRIT figure detailing chronology of activities by study phase.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4900929/v1/1d248eef1a3281a5d969e2fa.png"},{"id":73694355,"identity":"971e11a7-eab9-4be1-82e1-55d8848a97db","added_by":"auto","created_at":"2025-01-13 16:13:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":887964,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4900929/v1/5291b7b0-9745-4039-afa7-b5f72d6905a8.pdf"},{"id":64783549,"identity":"855a87ef-6560-4ba7-9f20-ce333218944a","added_by":"auto","created_at":"2024-09-18 18:58:59","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":41776,"visible":true,"origin":"","legend":"","description":"","filename":"LeeCOSLEPSPIRTIchecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-4900929/v1/d11362fd73c7a857d00830f7.docx"}],"financialInterests":"","formattedTitle":"Core Outcome Set development for LEPtospirosis trials (COS-LEP): a study protocol to develop a core outcome set for the evaluation of clinical therapeutic interventions for human Leptospirosis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLeptospirosis is a zoonotic bacterial infection occurring worldwide caused by \u003cem\u003eLeptospira interrogans\u003c/em\u003e. Although sporadically reported in high income countries, low-and-middle income countries bear a high burden of cases \u0026ndash; particularly in the South East Asian, Pacific, and Central and South American geographical areas.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) There are an estimated 1.03\u0026nbsp;million cases and 58,900 deaths due to Leptospirosis worldwide per year.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) More frequent climate catastrophes, poor infrastructure and social deprivation in these areas often precipitate outbreaks and epidemics.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe diagnosis of leptospirosis is difficult. Clinical manifestations vary from mild to severe disease requiring hospitalization and organ-supported care. Early manifestations are of an acute febrile illness (mimicking the presentation of various systemic infections in the tropics) with 10% of infected patients developing severe disease, including manifestations of hepato-renal failure and pulmonary haemorrhage requiring intensive hospital care.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe evidence for the management of leptospirosis particularly in severe disease, is limited by methodological inconsistency and a lack of established outcome measures to characterise disease and evaluate treatments. A 2012 Cochrane review of antimicrobial treatment included seven randomized trials spanning 1988\u0026ndash;2007. The outcome measures used varied from mortality, length of hospital stay, urinary culture clearance, resolution of biochemical changes, and defervescence (i.e. resolution of fever). Despite four trials including individuals with severe disease, no definitions of severity were provided. Duration of symptoms varied at presentation in each study. The review concluded there was insufficient evidence to advocate for, or against, the use of antimicrobials due to poor methodological quality or underpowered studies.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eSimilarly, when considering immunosuppressive therapies for severe leptospirosis disease, the last systematic review conducted in 2014 concluded there was insufficient data to establish efficacy.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Outcomes measures varied for these studies and included death, duration of ventilation, and duration of bleeding.\u003c/p\u003e \u003cp\u003eThe establishment of core outcome sets (COS) to define outcome measures is increasingly important to improve relevance of clinical trials to health service users and policy makers.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) This is particularly vital for research activities involving neglected diseases, where robust methods must be established to ensure reliably comparable trial results in a consistent manner.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) To date there have been no COS established specifically for the clinical management of leptospirosis. Standardization of measures would add consistency and lead to harmonization of leptospirosis therapeutic trials, thereby reducing waste in production and reporting of research. Furthermore, there are currently no established primary efficacy or safety outcomes for a definitive clinical trial of leptospirosis treatments, a significant contributing factor to current inconclusive systematic reviews regarding treatment and which represents a neglected research area.\u003c/p\u003e \u003cp\u003eThe aim of this study protocol is to describe a study framework that will define the minimum agreed upon set of outcomes for any clinical therapeutic trial in human leptospirosis.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eScope\u003c/h2\u003e\n \u003cp\u003eTo develop the COS-LEP protocol guidance set out by the Core Outcome Measures in Effectiveness Trials (COMET) initiative, and further specified by the Core Outcome Set-Standardised Protocol Items (COS-STAP) statement, were followed.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e) These provide standardised frameworks for the development of a COS. The COMET database (available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.comet-initiative.org/Studies\u003c/span\u003e\u003c/span\u003e) was searched for any pre-existing COS protocols for leptospirosis. When it was confirmed that there were none, this protocol was then registered (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cometinitiative.org/Studies/Details/2536\u003c/span\u003e\u003c/span\u003e). The planned start date of the study is July 2024, and the end date is October 2025. Technical review has been provided as part of the London School of Hygiene and Tropical Medicine (LSHTM) formal institutional Qualifying Exam process for PhD programs.\u003c/p\u003e\n \u003cp\u003eThe population that will be targeted with this COS are any individuals working in healthcare who regularly look after patients diagnosed with leptospirosis disease, researchers and policymakers involved in leptospirosis research, and individuals or groups representing individuals who are at risk of or who have been diagnosed with leptospirosis disease.\u003c/p\u003e\n \u003cp\u003eThe project will be carried out in five distinct phases, summarized in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The combined Phase 1 and 2 will consist of undertaking a systematic review of the literature for reported outcomes from quantitative and qualitative studies on the management of leptospirosis. In Phase 3, focused interviews to explore further outcomes of interest will be undertaken with healthcare providers and people at risk of leptospirosis infection. Phase 4 will consist of a multi-round Delphi survey process to begin constructing consensus around the outcome set. And Phase 5 will finalize the process with a consensus meeting.\u003c/p\u003e\n \u003cp\u003eThe schedule of enrolments and assessments is provided in \u003cstrong\u003eFig.\u0026nbsp;2\u003c/strong\u003e, as per Standard Protocol Items: Recommendations for Interventional Trials statement (SPIRIT).(\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e) A SPIRIT checklist is provided as a supplementary document (\u003cstrong\u003eSupplementary 1\u003c/strong\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eFigure 2 - SPIRIT figure detailing chronology of activities by study phase.\u003c/em\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003ePhase 1 and 2\u003c/h2\u003e\n \u003cp\u003ePhase 1 and 2 will establish existing knowledge about outcomes and methodology used in previous quantitative and qualitative studies looking at the treatment of human leptospirosis. To explore outcomes, a systematic review of outcomes from previously published quantitative and qualitative studies will be undertaken. The protocol for this systematic review has already been registered with the PROSPERO system in detail (PROSPERO ID CRD42023397461). In addition, systematic Cochrane Library reviews will be completed exploring methodology of all known clinical trials for human leptospirosis treatment, and determine efficacy and safety outcomes reported to date for evaluations of therapeutic interventions.(\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e) The output from all of these initiatives will provide the basis for options to put forward at later agreement stages.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy selection\u003c/h2\u003e\n \u003cp\u003eThe following databases will be included in the search: the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, LILACS, Web of Science Core Collection, Clinicaltrials.gov, and OpenSIGLE. The latter will be particularly important for the identification of grey literature sources. In each identified study, forward and backward reference searching will be used to identify further relevant publications.\u003c/p\u003e\n \u003cp\u003eAny study focusing on human leptospirosis will be included, across all age groups in a global distribution. Non peer-reviewed studies, most likely grey literature sources, may be considered. We will assess studies in batches chronologically by descending years in 5-year frames, until we achieve saturation in outcome types.\u003c/p\u003e\n \u003cp\u003eFull manuscripts will be prioritised, but abstract-only publications may be considered particularly if the full publication is unable to be obtained from the publisher or manuscript author. The search will not be initially limited by language, but studies may be excluded depending on which languages reviewing authors are able to speak. Further requirements, as identified by the PRISMA-S checklist, will be applied.(\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eData extraction\u003c/h2\u003e\n \u003cp\u003eStudies will be screened using the Covidence systematic review software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.covidence.org/\u003c/span\u003e\u003c/span\u003e). Title and abstract review, followed by full text review, will be performed by two reviewers. A third reviewer will be consulted if there is a disagreement between the first two reviewers that cannot be resolved through discussion.\u003c/p\u003e\n \u003cp\u003eData will be collected on the following;\u003c/p\u003e\n \u003cp\u003e1) Study design and sample size\u003c/p\u003e\n \u003cp\u003e2) Study population \u0026ndash; demographics, location\u003c/p\u003e\n \u003cp\u003e3) Intervention\u003c/p\u003e\n \u003cp\u003e4) Outcomes\u003c/p\u003e\n \u003cp\u003e5) Outcome measurements instruments and/or definitions provided by the authors for each outcome\u003c/p\u003e\n \u003cp\u003e6) Study conclusions\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eQuality Assessment\u003c/h2\u003e\n \u003cp\u003eThe primary author will assess the quality of included studies in accordance to the QualSyst tool.(\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e) Risk of bias in outcome reporting will be assessed according to the Outcome Reporting Bias in Trials (ORBIT) study classification system, and the ultimate goal will be to provide context to outcome measures rather than a basis for study exclusion.(\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eData Analysis\u003c/h2\u003e\n \u003cp\u003eData to be collected will be extracted verbatim. These will then be grouped based on terminology into group names, and then further grouped into domains.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) With respect to outcomes, as names and domains are dependent on the outcomes identified, these will not be defined a priori. A narrative synthesis of the included studies will be performed focused on the types of data collected defined above. The identified groupings will be mapped to the outcome framework proposed by the COMET group.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) Subgroup analysis will be considered if there are defined populations targeted by a particular outcome.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003ePhase 2 specific considerations\u003c/h2\u003e\n \u003cp\u003eCOMET handbook guidelines recommend the systematic review and identification of studies that specifically explore outcomes important to health service users.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) These may either be in the form of previously published Patient Reported Outcome Measures (PROMs) or studies employing qualitative methodology.\u003c/p\u003e\n \u003cp\u003eIt is not expected that a significant number of qualitative studies exploring treatment outcomes or studies establishing PROMs for leptospirosis have been previously published. If identified, a similar study selection and appraisal process as described in Phase 1 will be employed, focused on studies with a qualitative or mixed-methods design (where qualitative data collection and analysis methods were employed). With regards to data extraction, previously published methodology for extracting and analysing outcomes from studies reporting PROMs (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e) and qualitative literature (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e) will be used. Concepts and themes from excerpts will be categorized and tabulated to obtain frequency information. Categories will be mapped against the proposed COMET taxonomy, and if multiple domains are appropriate then two domains will be chosen as per guidance and precedence.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e\n \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\n \u003ch2\u003ePhase 3\u003c/h2\u003e\n \u003cp\u003eCentral to the COS-STAP statement is the definition of stakeholder groups who will be involved in the COS development process including how individuals will be identified, and the nature of their involvement.(\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e) This is particularly important as it is expected that identification of PROMs through the systematic review of qualitative literature may not yield many results.\u003c/p\u003e\n \u003cp\u003eTherefore Phase 3 will involve exploring outcomes of interest with healthcare providers and end-users directly affected by leptospirosis, to identify outcomes important to these groups, through the use of qualitative methods. This will, in addition, identify target population groups, explore acceptability of therapeutic interventions, and assess feasibility of conducting trial activities.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eParticipants Recruitment and Sample Size\u003c/h2\u003e\n \u003cp\u003eParticipant identification and recruitment will be done from collaborative institutional sites in the COS-LEP network. The institutions in the network are secondary/tertiary hospitals primarily found in areas endemic for leptospirosis \u0026ndash; the Philippines, Malaysia, Vietnam, New Caledonia, and Brazil. This may extend to other institutional sites in the same or different countries during the COS study (with appropriate local ethics agreements obtained prior to any enrolment activities).\u003c/p\u003e\n \u003cp\u003eParticipants who are healthcare providers that manage patients with leptospirosis will be identified and approached for recruitment. Additionally those at risk of leptospirosis, or who have made contact with healthcare services and for whom leptospirosis is included in the differential diagnosis, will also be identified and approached for recruitment. They will be provided with a patient information leaflet, as well as a verbal description of the study and its intention. After a 24 hour consideration period, they will be approached again and consented for enrolment.\u003c/p\u003e\n \u003cp\u003ePurposive sampling will be employed. Sample size calculations is a point of contention in qualitative studies, but methodological literature recommends that the reasoning behind any calculation be made transparent.(\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e) Recent qualitative studies exploring individual perspectives of participant\u0026rsquo;s experience with leptospirosis disease have contained\u0026thinsp;\u0026lt;\u0026thinsp;10 participants(\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e). Since focused interviews and thematic analysis will be used, and we will aim to recruit from international sites where collaborative institutional research is currently ongoing, we will aim to recruit at least 6 participants from each site. This may be revised should further sites be identified. The overall aim will be to achieve theoretical sufficiency, as defined as a point when a researcher has achieved sufficient or adequate depth of understanding to build a theory.(\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e) In addition, the total predicted sample size would approximate or supersede that of other COS-related published research using focused interviews.(\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eData Collection\u003c/h2\u003e\n \u003cp\u003eFocused interviews will be conducted, aided by a general topic guide. These will either be in person or remote/via teleconferencing means, the latter which now has a growing body of evidence supporting its use in qualitative methodology.(\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e) For those wishing to participate, but have limited fluency in English, attempts will be made to provide an interpreter subject to availability of personnel and/or funding. A very broad topic guide will be used, but the interview will be guided primarily by participants. Interviews will be audio recorded, and then anonymized and transcribed using the NVivo software (QRS International). Once all transcriptions are complete, interview recordings will be securely destroyed.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eData Analysis\u003c/h2\u003e\n \u003cp\u003eThematic analysis will be employed to summarize transcripts.(\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e) Features in the transcripts involving outcomes will be coded, subsequent codes collated into potential themes, themes revised and then defined. The generated themes will then be mapped to against the proposed taxonomy as stated in the COMET handbook, although consideration will be made to include if there is no adequate classification. Common themes in the classifications will be identified and outcome definitions that closely approximate each other will be removed.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003ePhase 4\u003c/h2\u003e\n \u003cp\u003eThe next stage of the COS development process will obtain a broad consensus on the proposed set of core outcomes identified in Phase 1\u0026ndash;3. The recommended methodology to accomplish this is the Delphi technique targeted at experts and other stakeholders through the use an evolving questionnaire and multiple rounds of consensus surveys.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eParticipant Recruitment and Sample Size\u003c/h2\u003e\n \u003cp\u003eThe stakeholders of interest for participation in surveys are patients (those who experienced leptospirosis disease), infectious diseases healthcare professionals (including medical microbiologist), non-infectious diseases healthcare professionals (including nephrology, pulmonology, intensive care, family medicine or other specialties), allied global health researchers (including epidemiologists, trialists, statisticians, and one health), and policymakers (both governmental and non-governmental). As many stakeholders as possible in a worldwide geographic spread will be included. Guidance on total number of stakeholders to be included is not based on statistical power but a pragmatic choice.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) We will seek to include sufficient participants per group to achieve good representation, but which will still allow for a consensus within group to be achieved.\u003c/p\u003e\n \u003cp\u003eStakeholders will be approached for recruitment using several communication avenues both in-person and virtual. Participation in surveys will be advertised to patients by direct means (at collaborative sites and those identified during Phase 3), dissemination through hospital communications at collaborative sites, through a project-specific website, and through social media. Researchers active in human leptospirosis will be identified from studies collated in Phase 1\u0026ndash;2 of the COS process. Healthcare professionals of any specialities will be identified by direct means at collaborative sites and through various professional networks of research teams. Policymakers will be identified through recommendation, existing national/international leptospirosis guidance, and from committee membership or involvement on various international leptospirosis societies. All participants will be requested to disseminate information through their various networks in order to increase uptake.\u003c/p\u003e\n \u003cp\u003ePotential participants expressing interesting in taking part in the survey will be directed to a study page provided by the Qualtrics platform that will provide study information in lay terms with full definition of medical terminology if used. Basic information such as demographics and suitability to participate will be assessed if potential participants wish to proceed. If these are met, then they will be able to proceed to the Delphi survey, with consent being gained electronically before undertaking the questionnaire.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eData Collection\u003c/h2\u003e\n \u003cp\u003eThe COMET Initiative has offered guidance that at least two survey rounds take place in order to incorporate feedback.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) The minimum number of rounds for this study will be two but will be extended if further consensus is required. The survey will be built using the Qualtrics survey software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.qualtrics.com\u003c/span\u003e\u003c/span\u003e) with a focus on lay language minimizing medical jargon (or with definitions included). We will attempt to engage with patients/members of the public identified from previous Phases of the COS-LEP study to develop and trial this lay terminology. Translations into other languages for particular groups will be explored depending on the participant groups included. Trials of the survey will be run amongst the study group and colleagues, and feedback incorporated back into the survey design.\u003c/p\u003e\n \u003cp\u003eThe COMET initiative suggests the use of the 9-point Likert scale where outcomes are graded in accordance to their level of importance, which is also the recommended framework by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e) This uses a scale between 1 and 9, with number 1\u0026ndash;3 defined as outcome of limited importance, 4\u0026ndash;6 outcome of importance but not critical, and 7\u0026ndash;9 meaning critical outcome. There will be an additional grade of \u0026ldquo;Unable to score\u0026rdquo; should participants feel they do not have the level of expertise to score a certain outcome.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) The order of outcomes to be scored might introduce a bias, and so outcomes order will be randomized as used in other COS studies.(\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e) Space will be provided at the point of rating each outcome and at the end of the questionnaire for participants to list additional outcomes not considered or to provide feedback on the list of outcomes. These will be reviewed between rounds by the study group and select patient representatives to determine classification within COMET taxonomy, how different the proposed outcome is from the existing listed outcome, and ultimately whether appropriate for inclusion in next round.\u003c/p\u003e\n \u003cp\u003eThere is wide variability in definition of whether individual outcomes meet a consensus for inclusion or exclusion of subsequent surveys, or at the end of the study. The COMET handbook does not provide a clear framework, but suggests more inclusive criteria be used in subsequent survey rounds should items be excluded in the intervening period.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) Relevant results from the first survey round will be presented to participants in the second round, presented graphically and by stakeholder group. This will enable participants to compare their prior scores within their stakeholder group and with other groups in the survey process. This study will adopt criteria used in previous COS studies, with less stringent criteria in earlier rounds.(\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e). Common in all rounds will be 1) the definition of consensus out from next round, which is any outcome with \u0026ge;70% of all participants rated 1\u0026ndash;3 (not important) for an outcome in any round; 2) any score not meeting inclusion or exclusion criteria will defined as no consensus; and 3) A participant\u0026rsquo;s score will be included for analysis if they complete 70% or more of outcomes.\u003c/p\u003e\n \u003cp\u003e\u0026bull; \u003cstrong\u003eRound 1.\u003c/strong\u003e Inclusion in next round \u0026ndash; any outcome rated 7\u0026ndash;9 (critical outcome) by \u0026gt;\u0026thinsp;50% of any participant and 1\u0026ndash;3 (limited importance) by no more than 15% of any single stakeholder group.\u003c/p\u003e\n \u003cp\u003e\u0026bull; \u003cstrong\u003eRound 2.\u003c/strong\u003e Inclusion - any outcome rated 7\u0026ndash;9 (critical outcome) by \u0026gt;\u0026thinsp;70% of any participant, and 1\u0026ndash;3 (limited importance) by no more than 15% of any single stakeholder group.\u003c/p\u003e\n \u003cp\u003eShould there remain a large number of outcomes following two rounds as decided by the study group a further third survey round may be conducted, with the outcome inclusion criteria to take forward to a consensus meeting being as for Round 2.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eAddressing Attrition\u003c/h2\u003e\n \u003cp\u003eThere is a risk of non-response by participants at all stages of the Delphi process, likely made greater by the international scope of the study. In order to decrease rate of non-responses, surveys will be kept open for four weeks and up to three reminder e-mails per round will be sent to participants with incomplete surveys. Details of current response rate and reminders of survey closing dates will be included in each message. If response rates remain low, consideration will be made for additional measures to increase this with consideration to time and funding. We will aim for 80% response per stakeholder group.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003eData Analysis\u003c/h2\u003e\n \u003cp\u003eThe distribution of outcomes for inclusion moving forward and degree of consensus will be summarized at the end of each round.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) Means and medians for each outcome will be calculated. The change of scores between rounds will be assessed by change in percentage, reduction in spread of scores by comparing standard deviations, and reductions in interquartile range.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) Metric will be reported for all participants, and inter-group between stakeholders.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003ePhase 5\u003c/h2\u003e\n \u003cp\u003eThe final phase of the COS development process will involve a consensus meeting where representatives of the various stakeholder groups can convene to discuss the results of the survey and decide on a final core set. Although we will aim for an in-person meeting, given the international scope of this study and the distribution of the stakeholder group, we may explore the possibility of conducting a hybrid approach of virtual and in-person meeting. If using a hybrid meeting approach, we will use guidance published by the COMET Initiative.(\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n \u003ch2\u003eParticipant Recruitment and Sample Size\u003c/h2\u003e\n \u003cp\u003eBuilding on standard proposed by the CODECS study, we will aim for 20 participants (4 from each stakeholder group to allow consensus to be achieved based on our revised consensus criteria) will be purposively selected for inclusion in a minimum of one consensus meeting.(\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e) We will adjust this number depending on interest and the practicalities/logistics of attending an in-person meeting. Although any participant may be included, to provide transparency in selection the final Delphi survey round will include a query of whether a participant is able to attend the consensus meeting. Consideration will also be made to include participants who did not respond or dropped out during the Delphi survey. We will explore the possibility of using break-out groups depending on total group size and availability of facilitators who can be trained to moderate as used in other COS development studies.(\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003eThe final number of participants and number of meetings will be a pragmatic decision based on expressed interest in participation, feasibility of joining a meeting, and ensuring representative input from all participants.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n \u003ch2\u003eData collection\u003c/h2\u003e\n \u003cp\u003eThe consensus meeting will consist of an introduction of the aims of the COS-LEP study, a summary of Phase 1\u0026ndash;4 activities and results, the discussions of the final set of outcomes, and a final vote on outcomes. The meeting will be recorded and take place over 2\u0026ndash;3 hours, but may be longer or divided into sessions depending on the number of participants, availability, and number of outcomes. Outcomes to be discussed will primarily be those that were selected in the Phase 4 Delphi survey, but outcomes which were excluded may be re-introduced and discussed again depending on participant interest.\u003c/p\u003e\n \u003cp\u003eWithin each stakeholder group\u0026thinsp;\u0026gt;\u0026thinsp;70% votes for either direct inclusion or exclusion of outcomes will be considered consensus. If there are issues with total number of participants or a limited number of stakeholder groups attending, we may consider using a threshold of \u0026gt;\u0026thinsp;70% across the entire group. These criteria have been proposed by the COMET Initiative as well as other COS developers such as the Outcome Measures in Rheumatology (OMERACT) group.(\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e) Results will be presented after voting, and reported by stakeholder group as well as across the entire group. Outcomes which are excluded or which do not meet the criteria of consensus can be reviewed by participants where there is opportunity to discuss any reason to disagree with these results. Should the number of included outcomes be large, a method to classify these following previous examples such as composite or tiered outcomes will be discussed in group.(\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e) Time permitting, the meeting may also be used to agree outcome definitions and define outcome measures.(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) The meeting will be transcribed and analysed using thematic analysis to explore participant\u0026rsquo;s perspectives on the agreed core outcomes, barriers to implementing, and any recommendation or suggestions for proceeding.(\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e) The outcome of Phase 5 will be the final core outcome set.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n \u003ch2\u003eDissemination of Results\u003c/h2\u003e\n \u003cp\u003eThe complete results of the COS study will be reported in international peer-reviewed open-access journals, international and national scientific and policymaking meetings, shared to clinical trial registries, and directly through all study group and participant networks. All study reports will follow reporting standards defined in the COS-STAR statement.(\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe COS-LEP study protocol describes the establishment of a COS for human interventional trials in leptospirosis disease. As highlighted earlier, the clinical management of leptospirosis is complicated by inconsistent trial methodology in published studies to date. To the authors\u0026rsquo; knowledge, this is the first COS developed for leptospirosis trials, and can serve as a template should such standards be required in the field of animal health.\u003c/p\u003e \u003cp\u003eThis COS will ensure that a minimum set of outcomes are included in any human leptospirosis trial. The use of these outcomes will have been agreed upon by healthcare professionals, policymakers, and patients. In this manner, the methodology of future trials can be harmonized and allow for easier and more meaningful comparison of results, particularly if undertaking meta-analysis. It will also be of benefit to the international treatment centres that manage leptospirosis cases and wish to record harmonised patient data.\u003c/p\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eTrial Status\u003c/h2\u003e \u003cp\u003eThis protocol version number is v11.0 (dated 9/8/2024). Systematic reviews quantitative and qualitative literature are in progress. Development of core outcome set is ongoing.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCOS; Core Outcome Set\u003c/p\u003e\n\u003cp\u003eCOMET;\u0026nbsp;Core Outcome Measures in Effectiveness Trials\u003c/p\u003e\n\u003cp\u003eCOS-STAP;\u0026nbsp;Core Outcome Set-Standardised Protocol Items\u003c/p\u003e\n\u003cp\u003ePROMs; Patient Reported Outcome Measures\u003c/p\u003e\n\u003cp\u003eCOS-STAR; Core Outcome Set\u0026ndash;STAndards for Reporting\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval, confidentiality, and consent to participate\u003c/h2\u003e\n\u003cp\u003eEthical approval has been received by the LSHTM Observational Research Ethics Committee (LSHTM Ethics Ref 29935). Approval for Phase 3 qualitative studies will be sought from relevant institutional review boards (IRB) prior to initiating study activities. Any planned protocol amendments will be communicated directly to the LSHTM Observational Research Ethics Committee and relevant local IRBs, with approval for amendments completed prior to any changes being instituted.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent to participate in interviews, Delphi surveys, and consensus meeting will be requested by the primary investigator when enrolling participants for this process. For study phases where participants will be enrolled (Phase 3 and 4), participants data will be anonymized through assigning a participant number as soon as enrolled on the study. A master spreadsheet will be kept during the study linking the participant to the study number, this will be kept password-protected with limitation to which research personnel can access.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter a maximum of 12 months from the end of data collection activities the master spreadsheet linking participants to study numbers will be destroyed (i.e. datasets with participant-identifying information will be destroyed). Anonymised datasets (e.g. anonymised transcripts) will be retained until the point where they are deposited in a data repository.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eAll authors will have equal access to data collected, and data will be deposited is a suitable repository at the end of the process. The protocol and individual studies will be made open-access.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis research was partially funded by the Nagasaki University WISE Programme in pursuit of a PhD qualification. The funding body did not contribute to the study.\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026rsquo; contributions\u003c/h2\u003e\n\u003cp\u003eNL is the lead author and principal investigator, conceived of the study, wrote the primary and subsequent drafts of the protocol, and approved the final draft. TE contributed to the conception of the study and contributed to drafts of the protocol. CS contributed to the conception of the study and contributed to drafts of the protocol. RB contributed to the conception of the study and contributed to drafts of the protocol. KA contributed to the conception of the study and contributed to drafts of the protocol. SS contributed to the methodology of Phase 2 and 3, and reviewed the final protocol draft. NB contributed to the Phase 4 and 5 methodology, and reviewed the final protocol draft.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eThe authors would like to acknowledge the establishment of the COS-LEP study group in this protocol. Subsequent published results of COS-LEP phases will be attributed to the COS-LEP study group. The authors would like to acknowledge Dr Sarah Gorst (COMET Initiative, Institute of Population Health, University of Liverpool) for their technical review and advice on overall protocol.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAuthor\u0026rsquo;s information\u003c/h2\u003e\n\u003cp\u003eNL is completing this project in pursuit of a PhD qualification on the Nagasaki University \u0026ndash; London School of Hygiene and Tropical Medicine Joint PhD Programme for Global Health. The COS-LEP project has undergone technical review by an LSHTM MPhil/PhD Upgrading Committee on 19/12/2023. TE, CS, RB, and KA are PhD supervisors for the project. SS and NB form part of the PhD advisory committee.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWilliamson PR, Altman DG, Bagley H, Barnes KL, Blazeby JM, Brookes ST, et al. COMET Handbook: Version 1 0 Trials. 2017;18(Suppl 3):1\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCosta F, Hagan JE, Calcagno J, Kane M, Torgerson P, Martinez-Silveira MS, et al. Global Morbidity and Mortality of Leptospirosis: A Systematic Review. PLoS Negl Trop Dis. 2015;9(9):0\u0026ndash;1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCosta F, Hagan JE, Calcagno J, Kane M, Torgerson P, Martinez-Silveira MS, et al. Global Morbidity and Mortality of Leptospirosis: A Systematic Review. PLoS Negl Trop Dis. 2015;9(9):0\u0026ndash;1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevett PN, Leptospirosis. Clin Microbiol Rev. 2001;14(2):296\u0026ndash;326.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrett-Major DM, Coldren R. Antibiotics for leptospirosis. Cochrane Database Syst Rev. 2012;2(2):CD008264.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRodrigo C, Lakshitha de Silva N, Goonaratne R, Samarasekara K, Wijesinghe I, Parththipan B, et al. High dose corticosteroids in severe leptospirosis: a systematic review. Trans R Soc Trop Med Hyg. 2014;108(12):743\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKirkham JJ, Gorst S, Altman DG, Blazeby JM, Clarke M, Devane D, et al. Core Outcome Set\u0026ndash;STAndards for Reporting: The COS-STAR Statement. PLoS Med. 2016;13(10):1\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOlayinka AT, Bourner J, Akpede GO, Okoeguale J, Abejegah C, Ajayi NA, et al. A standardised Phase III clinical trial framework to assess therapeutic interventions for Lassa fever. PLoS Negl Trop Dis. 2022;16(1):1\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKirkham JJ, Gorst S, Altman DG, Blazeby JM, Clarke M, Tunis S, et al. Core Outcome Set-STAndardised Protocol Items: The COS-STAP Statement. Trials. 2019;20(1):1\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilliamson PR, Altman DG, Bagley H, Barnes KL, Blazeby JM, Brookes ST, et al. COMET Handbook: Version 1 0 Trials. 2017;18(Suppl 3):1\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan AW, Tetzlaff JM, G\u0026oslash;tzsche PC, Altman DG, Mann H, Berlin JA et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTabei K, Win TZ, Kitashoji E, Brett-Major DM, Edwards T, Smith C, et al. Antibiotic prophylaxis for leptospirosis. Cochrane Database Syst Reviews. 2022;2022:2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMukadi P, Tabei K, Edwards T, Brett-Major DM, Smith C, Kitashoji E, et al. Antibiotics for treatment of leptospirosis. Cochrane Database Syst Reviews. 2022;2022:5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWin TZ, Tabei K, Mukadi P, Edwards T, Smith C, Lee N. Corticosteroids for treatment of leptospirosis. Cochrane Database Syst Reviews. 2022;2022(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRethlefsen ML, Kirtley S, Waffenschmidt S, Ayala AP, Moher D, Page MJ, et al. PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews. Syst Rev. 2021;10(1):39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGraham JW, Cumsille PE, Elek-Fisk E. Methods for Handling Missing Data. Res Methods Psychol. 2003;87\u0026ndash;114.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, Smyth R, et al. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews. BMJ (Online). 2010;340(7747):637\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMacefield RC, Jacobs M, Korfage IJ, Nicklin J, Whistance RN, Brookes ST et al. Developing core outcomes sets: Methods for identifying and including patient-reported outcomes (PROs). Trials. 2014;15(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGorst SL, Young B, Williamson PR, Wilding JPH, Harman NL. Incorporating patients\u0026rsquo; perspectives into the initial stages of core outcome set development: A rapid review of qualitative studies of type 2 diabetes. BMJ Open Diabetes Res Care. 2019;7(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRichardson E, McEwen A, Newton-John T, Manera K, Jacobs C. The Core Outcome DEvelopment for Carrier Screening (CODECS) study: protocol for development of a core outcome set. Trials. 2021;22(1):1\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoppe LE. Qualitative systematic reviews to increase the volume and diversity of patient perspectives included in the development of core outcome sets. Tuberculosis: a pilot study. Trials. 2015;16(S1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFroud R, Patterson S, Eldridge S, Seale C, Pincus T, Rajendran D et al. A systematic review and meta-synthesis of the impact of low back pain on people\u0026rsquo;s lives. 15, BMC Musculoskelet Disord. 2014.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKonstantina Vasileiou J, Barnett S, Thorpe T, Young. Characterising and justifying sample size sufficiency in interview-based studies: systematic analysis of qualitative health research over a 15-year period. BMC Med Res Methodol. 2018;18(1):1\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartins MHdaM, Spink MJP. Discourse Analysis of the Attributions of Causality and Responsibility for the Occurrence of Leptospirosis TT - An\u0026aacute;lise Discursiva das Atribui\u0026ccedil;\u0026otilde;es de Causalidade e Responsabilidade pela Ocorr\u0026ecirc;ncia da Leptospirose TT - An\u0026aacute;lisis Discursivo de Asignaciones. Paid\u0026eacute;ia (Ribeir\u0026atilde;o Preto, Online). 2020;30:e3027\u0026ndash;3027.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenschop J, Mocke S, Collins-Emerson JM, Lennan J, Weston JF. An exploratory qualitative enquiry into workers\u0026rsquo; experiences of leptospirosis and post-leptospirosis in Aotearoa New Zealand. N Z Med J. 2023;136(1570):30\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBraun V, Clarke V. Conceptual and Design Thinking for Thematic Analysis. Qualitative Psychol. 2021;9(1):3\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRichardson E, McEwen A, Newton-John T, Crook A, Jacobs C. Outcomes of Importance to Patients in Reproductive Genetic Carrier Screening: A Qualitative Study to Inform a Core Outcome Set. J Pers Med. 2022;12(8).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArchibald MM, Ambagtsheer RC, Casey MG, Lawless M. Using Zoom Videoconferencing for Qualitative Data Collection: Perceptions and Experiences of Researchers and Participants. Int J Qual Methods. 2019;18:1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBraun V, Clarke V. Usin thematic analysis in psychology. Qual Res Psychol. 2006;3(2):77\u0026ndash;101.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol. 2011;64(4):395\u0026ndash;400.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee SI, Eastwood KA, Moss N, Azcoaga-Lorenzo A, Subramanian A, Anand A, et al. Protocol for the development of a core outcome set for studies of pregnant women with pre-existing multimorbidity. BMJ Open. 2021;11(10):1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrown V, Moodie M, Tran HNQ, Sultana M, Hunter KE, Byrne R, et al. Protocol for the development of Core Outcome Sets for Early intervention trials to Prevent Obesity in CHildren (COS-EPOCH). BMJ Open. 2021;11(7):1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMitchell JW, Noble A, Baker G, Batchelor R, Brigo F, Christensen J, et al. Protocol for the development of an international Core Outcome Set for treatment trials in adults with epilepsy: the EPilepsy outcome Set for Effectiveness Trials Project (EPSET). Trials. 2022;23(1):1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGorst S, Barrington H, Brookes S, Chalmers J, Devane D, Fledderus A et al. Online consensus meetings for COS development: issues to consider [Internet]. [cited 2024 Mar 9]. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.comet-initiative.org/Downloads/Issues%20to%20consider%20for%20online%20consensus%20meetings.pdf\u003c/span\u003e\u003cspan address=\"https://www.comet-initiative.org/Downloads/Issues%20to%20consider%20for%20online%20consensus%20meetings.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eManera KE, Tong A, Craig JC, Brown EA, Brunier G, Dong J, et al. Standardized outcomes in nephrology\u0026mdash;peritoneal dialysis (SONG-PD): Study protocol for establishing a core outcome set in PD. Perit Dial Int. 2017;37(6):639\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoers M, Kirwan JR, Wells G, Beaton D, Gossec L, D\u0026rsquo;Agostino MA, et al. Developing core outcome measurement sets for clinical trials: OMERACT filter 2.0. J Clin Epidemiol. 2014;67(7):745\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeaton D, Maxwell L, Grosskleg S, Shea B, Tugwell P, Bingham CO III et al. The OMERACT Handbook Version 2.1 [Internet]. 2.1. Beaton D, Maxwell L, Grosskleg S, Shea B, Tugwell P, editors. OMERACT; 2021 [cited 2024 Mar 8]. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://omeract.org/handbook/\u003c/span\u003e\u003cspan address=\"https://omeract.org/handbook/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBourner J, Salam AP, Jaspard M, Olayinka A, Fritzell C, Goncalves B et al. The West Africa Lassa fever Consortium pre-positioned protocol for a Phase II/III adaptive, randomised, controlled, platform trial to evaluate multiple Lassa fever therapeutics. Wellcome Open Res [Internet]. 2023;8:122. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://wellcomeopenresearch.org/articles/8-122/v1\u003c/span\u003e\u003cspan address=\"https://wellcomeopenresearch.org/articles/8-122/v1\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eManera KE, Tong A, Craig JC, Brown EA, Brunier G, Dong J, et al. Standardized outcomes in nephrology\u0026mdash;peritoneal dialysis (SONG-PD): Study protocol for establishing a core outcome set in PD. Perit Dial Int. 2017;37(6):639\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Leptospirosis, core outcome set, clinical trial, systematic review, qualitative interview, Delphi survey","lastPublishedDoi":"10.21203/rs.3.rs-4900929/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4900929/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cu\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/u\u003e\u003cbr\u003e\nLeptospirosis is a zoonotic bacterial infection occurring worldwide. It is of particular public health concern due to its global distribution, epidemic potential and high mortality without appropriate treatment. The method for the management of leptospirosis, particularly in severe disease, is clouded by methodological inconsistency and a lack of standardized outcome measures.\u003c/p\u003e\n\u003cp\u003eThe study this protocol details aims to develop a core outcome set (COS) for leptospirosis research. A COS is a set of outcomes with international consensus as a minimum for reporting in future studies focusing on leptospirosis. Establishing a COS will contribute to harmonizing Leptospirosis treatment research and will be instrumental in constructing a high-quality evidence base to feed into a planned future rigorous international clinical trial on leptospirosis.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/u\u003e\u003cbr\u003e\nThe COS-LEP study will employ a COS development methodology standardized by the COMET initiative framework. This includes: 1) a systematic review of available quantitative and qualitative literature reporting therapeutic response and safety outcomes and measures; 2) focused interviews with healthcare professional and people treated for leptospirosis exploring outcomes of interests using qualitative methodology; 3) narrowing the choice of outcomes by international consensus using a Delphi survey process; and 4) undertaking a hybrid consensus meeting with key stakeholders to build the final COS.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003e\u003cstrong\u003eDiscussion\u003cbr\u003e\n \u003c/strong\u003e\u003c/u\u003eThis protocol describes the method to develop the first core outcome set for use in human leptospirosis studies. This will not only be a key feature in the design of a future definitive randomised controlled trial, but also provide a structure for clinicians and researchers collecting treatment cohort data in the various settings where leptospirosis is a public health issue.\u003c/p\u003e","manuscriptTitle":"Core Outcome Set development for LEPtospirosis trials (COS-LEP): a study protocol to develop a core outcome set for the evaluation of clinical therapeutic interventions for human Leptospirosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-18 18:18:48","doi":"10.21203/rs.3.rs-4900929/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2024-11-11T21:35:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-08-23T04:35:30+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-20T14:34:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-20T10:33:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-08-12T09:34:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"22e3fd05-e37d-439f-aa35-6bdf1e3ea05c","owner":[],"postedDate":"September 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-13T16:07:53+00:00","versionOfRecord":{"articleIdentity":"rs-4900929","link":"https://doi.org/10.1186/s13063-024-08713-6","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2025-01-06 15:57:08","publishedOnDateReadable":"January 6th, 2025"},"versionCreatedAt":"2024-09-18 18:18:48","video":"","vorDoi":"10.1186/s13063-024-08713-6","vorDoiUrl":"https://doi.org/10.1186/s13063-024-08713-6","workflowStages":[]},"version":"v1","identity":"rs-4900929","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4900929","identity":"rs-4900929","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}